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RheumThoughts: Screening and Overdiagnosis of ILD in RA


Hi everybody, I'm Mike Putman from the Medical College Wisconsin and today I would like to talk about over diagnosis in rheumatoid arthritis interstitial lung disease, which I'm going to call RA ILD for simplicity. Now first let me disclose something: I do not screen people for ILD with testing. I do take a thorough history and I have a much much lower threshold to get a CT scan if they have symptoms than I otherwise would.

What I want to talk about today, though, is screening with testing. Now, this is on my mind because the soon to be published ACR guidelines for patients with systemic autoimmune rheumatic diseases, which includes RA ILD, suggest that patients be screened with a high resolution CT scan and pulmonary function testing if they are, and I quote, "at increased risk". Now, we'll have to wait for the full manuscript to have this defined, but preliminary twittering suggest that it will be patients who are seropositive, older, or who have a higher BMI.

Now, I don't know about you, but that sounds like just about everyone to me - certainly not everyone, but a lot of people who I never would have done a high-res CT on or a PFT on in the past.

Why does this matter? I mean rheumatologists are used to testing for lots of different things, but this matters because of over diagnosis. Overdiagnosis is not something that I think we talk about as much. Usually we're worried about not diagnosing or under diagnosing or misdiagnosing, but over diagnosing bothers me as well. Over diagnosing is when you diagnose people with a disease that never would have caused them symptoms or negatively affected their thriving or longevity - that's over diagnosis.

In this case, if we start doing a lot of these high-res CTs and pulmonary function tests on people, I'm 100 percent sure that some of these people will be over diagnosed with ILD. Most doctors historically, and I would guess most doctors today, are not desperately searching for ILD and when we start changing those practice patterns that's what you're going to get.

Today when we find someone with rheumatoid arthritis, we start them on a DMARD that has an activity against their disease. Their joints often get better, their skin gets better, and critically, I would assume that any small simmering lung inflammation that had yet to cause symptoms also gets better.

Thus you know, some of these patients who we have been historically treating and who do well probably had ILD in the all-knowing deity sense of the word, but because it never got a work up for it, they never had it on their problem list, right? They never suffered the existential dread that comes with knowing they have a potentially terminal lung condition. They never had to undergo repeat high-res CTs and PFTs every three months as the guidelines also suggest, and they never had to write on their insurance forms, tell their family that they may need a lung transplant in some distant tragic future - they never had to go through any of this junk. In short, a lot of the patients who you have treated in your career with rheumatoid arthritis where you didn't get all this screening probably had a little bit of it, but they got better and you never knew and your patient lived a long happy life.

That's the future that you want for a lot of your patients.

Now overdiagnosis itself is a problem, but this gets worse because. Not only is this over diagnosis finding these subtle ILDs that probably never would have done anything but it will also inevitably lead to something that I'm going to call inadequate therapy. How could diagnosing ILD result in inadequate therapy? Well it's pretty easy, let me tell you.

So the treatment recommendations from the same guideline project for RA ILD are frankly kind of befuddling. I'm just going to talk about one aspect of that data, which is the first line recommended treatments for RA ILD.

Now one of the agents they say is rituximab, which seems reasonable - I mean a little aggressive. You know the patient that you had who comes in with you know normal RA and you don't screen them. You'll start them on Methotrexate or a TNF inhibitor and I imagine they do quite well - that's a lot less risky from an immune system perspective than rituximab. But, you know, okay fine so they have ILD you start them on rituximab, I'm okay with that because at least rituximab works for RA.

But there are other two first-line options I think are a little bit silly. The first one is mycophenolate. Mycophenolate is a moderately defensible choice, you know, it's good drug overall and one that I've considered for patients with RA albeit with another drug that has efficacy in RA. MMF by itself does not have good efficacy in RA, is not likely to help your patients joint symptoms, and there's some only some observational studies that it may be efficacious in RA ILD. But the bottom line is that this is not a great ILD drug. It's a kind of reasonable lung drug and it's just it's scary to me that patients will get it in the first line.

Then that brings me to the third agent that they recommend as first line, which is azathioprine. Now I'm sorry to say this, but azathioprine is the worst. To its credit, it does have an RCT level data in ILD. The PANTHER-IPF trial enrolled patients to placebo or the combination of prednisone, acetylcysteine and azathioprine. Alright, should that make you reassured we have an RCT? No absolutely not! So PANTHER-IPF was stopped early because patients were dying in the treatment group and, I quote, the author said there was no evidence of physiological or clinical benefit. So let me repeat that: the only RCT we have to date for azathioprine and ILD where it was part of a cocktail, probably resulted in people dying and did not work. So I I don't understand why people think this is a good drug for the lungs. It's also not a good drug for RA in general. The 2016 ACR guidelines for the management of RA unceremoniously dropped azathioprine in a footnote of a table alongside of minocycline and gold. It's just in this category of treatments that we're just not doing for rheumatoid arthritis

To bring this all together, I highly recommend reading Richard Conway's recent piece on RheumNow. It was entitled ACR RA ILD Treatment Guidelines - What Were They Smoking?! He covers some of the other considerations and some of their concerns that I have.  I wanted to just lay out the case here today against screening aggressively. This is very much going to identify people who probably never would have had any issues with their lungs. It's going to put them on a treatment pathway that includes rituxmab - pretty aggressive - microfenolate - not a great RA drug - and azathioprine - the worst.

I understand the need for clinical practice guidelines in RA, but rheumatologists really need to think twice before listening to these guidelines and operationalizing them.


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Mike Putman is an Assistant Professor of Medicine at the Medical College of Wisconsin, where he is the Medical Director of the Vasculitis Program and maintains an active practice in general rheumatology. He is involved in education and currently serves as the Associate Program Director for Rheumatology, Associate Program Director for Internal Medicine, and medical school co-director for Hematology and Immunology. His research interests include clinical trials in vasculitis, “big data” epidemiology, and meta- research. He is also an Associate Editor of the journal Rheumatology and hosts the Evidence Based Rheumatology podcast.